Cynthia Hawkins. Division of Pathology, Labatt Brain Tumour Research Centre, The Hospital for Sick Children, University of Toronto, Canada

Transcription

1 Cynthia Hawkins Division of Pathology, Labatt Brain Tumour Research Centre, The Hospital for Sick Children, University of Toronto, Canada

2 To apply a practical diagnostic approach to pediatric high grade glioma To review molecular pathways relevant to pediatric high grade glioma To appreciate relevant differences between pediatric and adult high grade glioma

3 Diagnostic dilemma: High vs. low grade glioma Overview of clinical, genetic and histologic features that can help Key points: Pediatric HGG adult HGG Location of tumor

4 6 y.o. boy presented with right temporal headache which increased in frequency and intensity Vomiting and the onset of fever led to a CT scan; however, because of artifact, this was inconclusive His symptoms progressed, he was irritable, tired, developed blurred vision and a head tilt to the right Headaches now localized to the occipital region

5 Axial T2 Axial T1 +C Axial T1 +C A large mass lesion extending along the left aspect of the brainstem. DDx exophytic brainstem glioma, PNET or extra-axial neoplasm infiltrating the adjacent brainstem. Ependymoma considered less likely given the cystic changes.

6 Leading cause of cancer-related morbidity and mortality in pediatric years 2 nd most common childhood cancer and most frequent solid tumour pilocytic astrocytoma diffuse astrocytoma anaplastic astrocytoma CBTRUS CNS tumour survival data yr 2 yr 5 yr 10 yr glioblastoma

7 Adults > Children Hemispheric Thalamus Cerebellum Brainstem Children > Adults Spinal cord

8 Diffuse astrocytoma (II) Anaplastic astrocytoma (III) Glioblastoma (IV) Pilocytic astrocytoma (I) Pilomyxoid astrocytoma (II) Pleomorphic xanthoastrocytoma (II) Subependymal giant cell astrocytoma (I) Gliomatosis cerebri (II-III)

9 Microscopic Pathology WHO 2007 Classification Key histologic features What do we think we know or are likely to learn about PLGA? Diagnostic/ Prognostic Biomarkers Therapeutic Biomarkers What s on the horizon?

10 WHO grade I Most common glioma in childhood Typically present in 1 st two decades Location - Throughout neuraxis Histology: Biphasic pattern: Compact areas with bipolar cells and Rosenthal fibers Loose areas with multipolar cells, microcysts and EGBs Rare mitoses, hyperchromatic nuclei, vascular proliferation, necrosis and meningeal infiltration are not signs of malignancy Diagnostic challenge vs. GBM

11 Must be defined as infiltrative Diagnostically challenging morphologic overlap with non-infiltrative astrocytomas (PA, PXA) as well as ganglioglioma In some cases, particularly with small biopsies necessitated by the location of the tumor, accurate grading is not possible and the more generic term low grade astrocytoma is used

12 Unlike in adults, where low grade diffuse astrocytomas almost inevitably progress to higher grade lesions, this is only rarely the case in pediatrics

13 WHO grade distinguishing between grade I/ pilocytic astrocytomas and grade II/ diffuse astrocytomas in the cerebellum is NOT of prognostic significance in the pediatric population For incompletely resected tumor in other locations, identification of diffuse astrocytoma is prognostic, but not always possible to do so

14 PLGA and RAS-MAPK pathway High rate of optic pathway PLGAs in NF1 patients, suggesting RAS-MAPK pathway activation BRAFV600E mutation BRAF fusion/duplication

15 Supratentorial 18% 33% Optic pathway 54% 15% 51% 2% 3% 74% Cerebellum BRAF fusion Non-cerebellar infratentorial BRAFV600E Horbinski. JNEN 2013

16 BRAF Alteration PA PMA PXA GG DA HGG BRAF fusion 67% 50% 0% 21% 12% 0% BRAFV600E 6% 8% 74% 19% 10% 13% Horbinski. JNEN 2013

17 Microscopic Pathology WHO 2007 Classification Key histologic features What do we think we know or are likely to learn about HGA? Diagnostic/ Prognostic Biomarkers What s on the horizon?

18 WHO grades III (AA) and IV (GBM) Less common than low-grade astros Molecularly and biologically distinct from adult counterparts Usually are not the result of progression from low grade counterpart (vs adult) High grade astro vs mixed glio-neuronal tumours vs PNET

19 Microscopic features Anaplastic cellular glioma Marked nuclear atypia and brisk mitotic activity +/- necrosis, +/- vascular-endothelial proliferation (grading) GBM may have highly variable histology (sarcoma, PNETlike)

20 WHO grade Unequivocal diagnosis of a WHO grade III or IV astrocytoma is associated with a poor outcome compared with a WHO grade I or II diagnosis Prognostic role for distinguishing grade III from grade IV astrocytoma in the pediatric population is less clear

21 MIB1 association between higher MIB-1 and poorer overall survival, precise cut-off is not the same between studies conservatively, MIB-1 labeling index >36% should be considered as an indicator of poor overall survival in pediatric high grade astrocytoma

22 P53 controversial largest study to date supports the conclusion that p53 immunopositivity is associated with a poorer 5 year progression-free survival in glioblastomas in children >3 years of age this finding has not been replicated

23 MGMT Association between MGMT expression or methylation and outcome is less clear than in adults Currently no study shows this to be an independent predictor of outcome IDH1R132H Rarely found in pediatric gliomas except older teenagers

24 H3F3A replication-independent histone 3 variant 3.3 two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications HIST1H3B/C Replication-dependent histone 3 variant 3.1 K27M only

25 Hemispheric GBM 14% 3% 42% Thalamic GBM 13% 66% H3.3K27M DIPG H3.3G34R/V H3.1K27M

26 Mean overall survival: K27M-H years ((±0.48)) WT 4.59 years (±5.55) (p=0.0008)

27 ATRX belongs to the SWI/SNF family of chromatin remodeling proteins Mutated/ lost in 15-30% of pediatric HGG Associated with ALT phenotype (TERT promoter mutations rare in pediatric HGG) SETD2 histone methyltransferase specific for H3K36 Mutated in 15% of pediatric HGG (mutually exclusive with H3F3AG34R/V)

28 EGFR 5% PDGFRA 30% FGFR 0% PTEN 5% PIK3CA/ PIK3R1 20% RAS 0% NF1 20% AKT pathway BRAF 10% MAPK pathway MDM2 5% MDM4 5% TP53 35% CDK4 3% CDKN2A/B 15% cyclins 5% CDK6 5% Senescence apoptosis RB1 10% Cell cycle control

29 Pediatric high grade gliomas need to be considered as a distinct entity from adult tumors (rare EGFR, IDH, MGMT) The location of the tumor is important (pontine vs not) Pilocytic astrocytomas may have necrosis (but not pseudopalisading), vascular endothelial proliferation and occasional mitotic figures

30 Molecular testing for BRAF and histone alterations can help distinguish high grade form low grade astrocytoma in children Mutational status of H3.3/ H3.1 may be more helpful than histologic appearance alone in identifying patients expected to have a poor clinical outcome at presentation

31 To apply a practical diagnostic approach to pediatric high grade glioma To review molecular pathways relevant to pediatric high grade glioma diagnosis To appreciate relevant differences between pediatric and adult high grade glioma

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33 References for Pediatric High Grade Glioma 1. Fried I, Hawkins C, Scheinemann K, Tsangaris E, Hesselson L, Bartels U, Huang A, Laperriere N, Dirks P, Bouffet E, Tabori U. Favorable outcome with conservative treatment for children with low grade brainstem tumors. Pediatric blood & cancer 2012;58: Horbinski C. To BRAF or not to BRAF: is that even a question anymore? Journal of neuropathology and experimental neurology 2013;72: Horbinski C, Nikiforova MN, Hagenkord JM, Hamilton RL, Pollack IF. Interplay among BRAF, p16, p53, and MIB1 in pediatric low-grade gliomas. Neuro-oncology 2012;14: Schwartzentruber J, Korshunov A, Liu XY, Jones DT, Pfaff E, Jacob K, Sturm D, Fontebasso AM, Quang DA, Tonjes M, Hovestadt V, Albrecht S, Kool M, Nantel A, Konermann C, Lindroth A, Jager N, Rausch T, Ryzhova M, Korbel JO, Hielscher T, Hauser P, Garami M, Klekner A, Bognar L, Ebinger M, Schuhmann MU, Scheurlen W, Pekrun A, Fruhwald MC, Roggendorf W, Kramm C, Durken M, Atkinson J, Lepage P, Montpetit A, Zakrzewska M, Zakrzewski K, Liberski PP, Dong Z, Siegel P, Kulozik AE, Zapatka M, Guha A, Malkin D, Felsberg J, Reifenberger G, von Deimling A, Ichimura K, Collins VP, Witt H, Milde T, Witt O, Zhang C, Castelo-Branco P, Lichter P, Faury D, Tabori U, Plass C, Majewski J, Pfister SM, Jabado N. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012;482: Sturm D, Bender S, Jones DT, Lichter P, Grill J, Becher O, Hawkins C, Majewski J, Jones C, Costello JF, Iavarone A, Aldape K, Brennan CW, Jabado N, Pfister SM. Paediatric and adult glioblastoma: multiform (epi)genomic culprits emerge. Nature reviews Cancer 2014;14: